Argyrios Ziogas

A framework for assessing interactions for risk stratification models: the example of ovarian cancer

Abstract Generally, risk stratification models for cancer use effect estimates from risk/protective factor analyses that have not assessed potential interactions between these exposures. We have developed a 4-criterion framework for assessing interactions that includes statistical, qualitative, biological, and practical approaches. We present the application of this framework in an ovarian cancer setting because this is an important step in developing more accurate risk stratification models. Using data from 9 case-control studies in the Ovarian Cancer Association Consortium, we conducted a comprehensive analysis of interactions among 15 unequivocal risk and protective factors for ovarian cancer (including 14 non-genetic factors and a 36-variant polygenic score) with age and menopausal status. Pairwise interactions between the risk/protective factors were also assessed. We found that menopausal status modifies the association among endometriosis, first-degree family history of ovarian cancer, breastfeeding, and depot-medroxyprogesterone acetate use and disease risk, highlighting the importance of understanding multiplicative interactions when developing risk prediction models.

Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis

Abstract Background The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC. Methods LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source. Results LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes. Conclusions LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies

Abstract Background Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated. Methods A pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses. Results Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer. Conclusions Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.

High Prediagnosis Inflammation-Related Risk Score Associated with Decreased Ovarian Cancer Survival

Abstract Background: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects. Methods: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data. Results: There was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03–1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11–1.54). Conclusions: A higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival. Impact: Given that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.

Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

AbstractBackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.ConclusionsCNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

Modification of the Association Between Frequent Aspirin Use and Ovarian Cancer Risk: A Meta-Analysis Using Individual-Level Data From Two Ovarian Cancer Consortia

PURPOSE Frequent aspirin use has been associated with reduced ovarian cancer risk, but no study has comprehensively assessed for effect modification. We leveraged harmonized, individual-level data from 17 studies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across subgroups of women with other ovarian cancer risk factors. METHODS Nine cohort studies from the Ovarian Cancer Cohort Consortium (n = 2,600 cases) and eight case-control studies from the Ovarian Cancer Association Consortium (n = 5,726 cases) were included. We used Cox regression and logistic regression to assess study-specific associations between frequent aspirin use (≥ 6 days/week) and ovarian cancer risk and combined study-specific estimates using random-effects meta-analysis. We conducted analyses within subgroups defined by individual ovarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of risk factors (0, 1, and ≥ 2). RESULTS Overall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20), with no significant heterogeneity by study design ( P = .48) or histotype ( P = .60). Although no association was observed among women with endometriosis, consistent risk reductions were observed among all other subgroups defined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, all P-heterogeneity > .05), including women with ≥ 2 risk factors (relative risk, 0.81; 95% CI, 0.73 to 0.90). CONCLUSION This study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent aspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer risk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of principle that chemoprevention programs with frequent aspirin use could target higher-risk subgroups.